Genetics

Question 1

the human genome - how many nts, how many genes (what percent of genome is genes)

Answer 1

unique sequence of 3 billion nts (or base pairs), with 20,000-25,0000 genes comprising 1-2% of total genome and many other regions involved in reg/control; mammal genomes not as large as some plants/protists/amphibians etc

human genomes 99.9% identical; at any given genomic locus, all individuals are related on a tree, where on one branch perhaps a G-T mutation occurred, so all other branches G and all from that branch T; diffs between individual correspond to mutations which have occurred since most recent common ancestor eg humans/chimps 1.37% diff, from gorillas 1.75% diff, from orangutans 3.4%

Question 2

genome evolution - 3 forms of selection, what is genetic drift, how does pop size influence drift, 2 models used to model drift, is selection better or worse in smaller pops and implication for deleterious alleles

Answer 2

natural selection: +ve favours new beneficial allele, negative/purifying favours existing allele, balancing (rare) favours presence of 2 or more alleles

germline mutation introduces new allele at low freq; genetic drift is random variation in allele freq from one gen to next; genetic drift is stronger in smaller pops leading to more loss of genetic diversity

in wright-fisher model of genetic drift, in diploid pop of N individuals, 2N copies of gene with allele freqs q and p, assume generations don’t overlap and each copy of each gene in new gen drawn randomly from all copies of gene in old gen: probability of getting k copies of allele with freq p in last gen is 2N!/k!(2N-k)! x P^k x q^(2N-k); moran model assumes overlapping gens, gives similar results to wright-fisher but genetic drift runs twice as fast (also moran model more complex to computer simulate as needs more time steps); selection is less effective in smaller pops so even deleterious alleles can inc in freq

Question 3

effects of genetic drift - definition, one dec and one inc due to what phenomena and effect of population size on these phenomena, 3 world examples of this

Answer 3

genetic drift: random changes in allele freq from one gen to next; genetic diversity decreases and homozygosity increases over time due to allele fixation (freq reaches 100%) or loss (freq reaches 0%) with these effects greater (diversity lost more quickly) in smaller populations, and moderately deleterious mutations undergoing negative selection can fix in a small population; in small/isolated pops there is increased prevalence of deleterious pathogenic alleles and less effective negative selection eg amish/hutterite/mennonite communities in north america have inc prevalence of microcephaly, Tay-sachs disease in ashkenazi jews; finnish disease heritage: 33 monogenic diseases more freq in finland than any other population

Question 4

chi squared and genetics - purpose of using the test; starting assumption, if thi is true what should allele count be; how chi squared calculated and what it will show you once calculated; 2 steps for chi squared in GWAS, how can population structure introduce error

Answer 4

to determine if association between allele and disease: assume no link, if no link, allele count in cases/controls should reflect overall pop (so allele freq x number of controls); then record how the data actually is

chi squared statistic is normalised measure of diff between observed and expected values; (observed value - expected value)^2/expected value; calculate p value using your degree of freedom can see whether difference is due to random variation or if link exists; assumes no bias in data collection etc

in GWAS: calculate chi squared values for many loci, rank them in size of x^2 value and top ones can be considered further; convert chi squared values into p values and set genome wide significance threshold eg 10^-8 (also express as -log10 p >8) and consider all loci with p values less than this; large sample size (thousands) needed to get sufficient statistical power for most phenotypes; population structure can lead to false signals of association: if cases/controls have diff genetic ancestry, will find genetic variants associated with that

Question 5

mendellian genetics - 3 principles, how to tell if one plant is hom/het; 8 reasons for frequency of trait to not be what is predicted from those 3 principles

Answer 5

principles of segregation (2 alleles, one from each parent, random transmission), independent assortment (except linkage), dominance: back cross of F1 with homozygous recessive to see if dominant is homo/hetero

alterations to frequency if: genotype early lethal, imprinting, epistasis (genes interact to produce phenotype eg ee for blonde labs, usually BB/bb that decides if Ee or EE), dynamic mutation, variable penetrance/expressivity (not all show phenotype, show phenotype to varying degree), linked inheritance, co-dominance (homo/hetero show diff phenotype)

Question 6

genetic linkage - what it is, how to test, what is a centimorgan, what did it allow for, nowadays what do we do

Answer 6

loci close together will co-segregate so have lower chance of recombination, test if linked using chi squared with null hypothesis that they aren’t linked (ie same recombination frequency as with gene on another chromosome), exception to independent assortment; recombination% (ie % chance they will become separated) converts to distance eg 1% = 1 centimorgan (doesn’t convert to actual distance as eg centromeres less chance of recombination happening)

this allows distance and mapping of genome using markers at known loci to establish candidiates for monogenic disease causing variants then checking to see if mutated in patient; nowadays we can sequence genome and use actual physical distances, look for mutations in patient’s genome etc

Question 7

genetic tests - 2 common ones; karyotype what it is, 5 detects and 2 misses; fast-FISH what it is, detects 2 and misses 3; QF-PCR what it is, detects 2 and misses 3; microarray what it is, how resolution varies, detects 4 and misses 3;

Answer 7

most children with possible genetic condition will have a genetic test, and most commonly this will be chromosomal microarray or WGS (with important exceptions)

karyotype:
A cytogenetic test to visualise the number and structure of chromosomes
Detects:
Large deletions and duplications (>5Mb)
Chromosomal translocations/rearrangements
Aneuploidies (abnormal number of chromosomes)
Can detect chromosomal mosaicism ~10%
Misses:
Small-moderate sized deletions and duplications (~<5Mb)
Sequence variants, etc.

Fast-FISH
Fluorescence in situ hybridisation (FISH) is a cytogenetic test, which uses chromosome specific probes to identify the common aneuploidies
Detects:
‘Fast-FISH’ is typically the quickest way to detect the common aneuploidies (e.g. Down Syndrome, Edwards Syndrome, Patau’s Syndrome) in the post-natal setting
Some labs will report sex chromosome aneuploidies (e.g. Turner Syndrome, Kleinfelter Syndrome)
Misses:
Copy number variants (microdeletions and duplications) unless using targeted probes
Chromosomal translocations, sequence variants, etc.

QF-PCR
Quantitative Fluorescence PCR is a molecular genetic test which uses chromosome specific markers to identify the common aneuploidies. It is typically used in the pre-natal setting, but some labs may offer post-natally.
Detects:
QF-PCR is typically used in the pre-natal setting to detect the common aneuploidies (e.g. Down Syndrome, Edwards Syndrome, Patau’s Syndrome) in the post-natal setting
Some labs will report sex chromosome aneuploidies (e.g. Turner Syndrome, Kleinfelter Syndrome)
Misses:
Copy number variants (microdeletions and duplications) unless using targeted probes
Chromosomal translocations, sequence variants, etc.

Micro-array
Cytogenetic test, which uses probes across the genetic code to detect imbalances (copy number variants).
The resolution of an array (the size of deletions and duplications it can detect) varies across different regions of the genome, depending on probe density.
SNP array and array CGH are both types of microarray, but are performed using different laboratory techniques.
Detects:
Microdeletions (e.g. 22q11.2 microdeletion, William’s syndrome) and microduplications
Aneuploidies
Can detect chromosomal mosaicism ~>10%
A SNP-based array can detect unipaternal isodisomy, triploidy and loss of heterozygosity
Misses:
Balanced translocations/rearrangements
Small deletions and duplications (~<50Kb)
Sequence variants, etc.

Question 8

genetic tests part 2 - exome sequencing what it is, 2 ways to analyse, how second way is approached, detects 3 things, misses 9; whole genome sequencing what it is, what panels are, detects 2, misses 3; 6 times specific assays needed instead of general tests

Answer 8

Exome sequencing
A molecular genetic test, which sequences the coding portion of the genetic code (~1% of the entire genome).
An exome can be analysed as a trio (child and parents analysed together) or as a singleton/duo.
The results of a trio exome are usually filtered using an “agnostic approach” (concentrating on variants which are de novo, recessive, or X-linked). A duo or singleton exome is usually filtered using one or more virtual panels.
Detects:
Sequence variants (“spelling mistakes”) in the coding genes
Some exome testing techniques can detect intragenic (small) deletions and duplications
Some exome testing techniques can detect copy number variants
Misses:
A trio exome, which uses an “agnostic” filtering approach, may miss autosomal dominant inherited disorders
An exome which is filtered using virtual panels, may miss variants in genes not included on the panels
Non-coding variants, microdeletions and duplications, aneuploidies, triplet repeat disorders, disorders of methylation/imprinting, mitochondrial mutations, etc.
An exome may miss low level mosaicism, depending on read depth

Whole genome sequencing
A molecular genetic test which sequences the entirety of the genetic code (~3 billion base pairs).
Typically the results of the genome are filtered using one or more virtual panels ie a panel for intellectual disability, another for hyperinsulinism etc - you will generally order a panel rather than the whole test.
As above, the results of a trio genome are usually filtered using an “agnostic approach” (concentrating on variants which are de novo, recessive or X-linked).
Detects:
Sequence variants in both coding and non-coding areas of the genome
Some genome testing techniques can detect intragenic (small) deletions and duplications, and copy number variants
Misses:
A genome, which is filtered using virtual panels, may miss variants in genes not included on the panels
Triplet repeat disorders, disorders of methylation, mitochondrial mutations, etc
A genome may also miss low level mosaicism, depending on read depth

Some conditions need specific assays as none of the above will pick them up, eg:
Methylation disorders (e.g. Prader Willi, Angelman, Beckwith Weidemann and Russell Silver Syndrome)
Spinal Muscular Atrophy
Triplet repeat and other short tandem repeat disorders (e.g. Myotonic dystrophy, Fragile X, Friedrich ataxia, most spinocerebellar ataxias)
Disorders caused by variants in the mitochondrial genome
Uniparental disomy
Deep sequencing on DNA extracted from an affected tissue (e.g. somatic mosaicism in PIK3CA-related disorders)

Question 9

chromosomal microarray

Answer 9

A microarray is a special genetic test that looks in detail at a person’s chromosomes to see if there are any extra or missing sections which might account for problems they have been experiencing

It can identify:

large deletions and microdeletions and large duplications and microduplications
most abnormalities of chromosome number (eg Down syndrome)
unbalanced rearrangements of chromosome (eg complex insertions or deletions).
However, it does not identify:

single gene mutations
fragile X syndrome (FXS)
balanced rearrangements (eg: translocations and inversions).

There are two different ways of performing microarray testing: array comparative genomic hybridisation (aCGH) and single nucleotide polymorphism array (SNP array).

aCGH
Patient and reference DNA are labelled with different coloured fluorescent dyes (usually red for reference and green for patient DNA).
An array slide is spotted with oligonucleotide DNA probes – small molecules of DNA that are designed to hybridise with a particular section of the genome. Probe distribution around the genome is not even. The probes provide ‘backbone’ coverage around the genome, and additional probes may be present in gene rich regions, syndrome regions or specific genes of interest.
Patient and reference DNA are washed over the array slide and bind competitively to the probes.
The array slide is washed and scanned, and the fluorescence emitted at each probe location is measured.
Computer software then analyses the data:
Yellow: equal patient and reference DNA present.
Red: more reference DNA than patient DNA, therefore a deletion is present.
Green: more patient DNA than reference DNA, therefore a duplication is present.

A SNP array slide is spotted with allele-specific DNA probes targeting regions in which there is SNP variation between individuals.
Patient DNA is hybridised to the array slide and binds to the probes.
The array slide is scanned, and the fluorescence emitted at each probe location is measured.
The fluorescence emitted is dependent on which alleles are present in the patient at the SNP site targeted by the probe.
Computer software then analyses the data, identifying regions in which copy number variation is present by looking at which nucleotides are present at each SNP location.

CMA tests should be considered by any clinician evaluating a child with otherwise unexplained developmental delay, intellectual disability, ASD, or congenital anomalies

common conditions tested for using chromosome microarray include: digeorge syndrome, prader willi and angelmans, williams syndrome, ASD (16p11.2 deletion), sotos, cri du chat, charcot marie tooth and more

Question 10

3 important rules to cover when consenting for genetic test, 2 challenges for testing (inc how many de novo mutations we have), what is a trio/why do it, general what 2 bottles to send

Answer 10

Non-diagnosis: There is no single genetic test that can diagnose all genetic conditions. Even very extensive genetic tests (eg exome or genome sequencing) will miss underlying genetic diagnoses. A “normal” genetic test result cannot entirely rule out an underlying genetic diagnosis.
“Grey results” / Variants of uncertain significance: We all carry thousands of genetic variants (“spelling mistakes”) across our genetic code. Sometimes when the lab detect a variant, it can be difficult for them to work out if the variant is causing a problem (“pathogenic”) or if it is harmless (“benign”). These “grey results” can sometimes cause additional worry or anxiety.
Incidental findings, including unexpected family relationships: It is possible that genetic testing can detect variants which do not explain the original reason for the test, but are still relevant for health (an “incidental finding”). The laboratory do not usually go “looking for” incidental findings, but if they encounter an incidental finding, they may report this back. In general, the lab will only report incidental findings where something can be done (e.g. cancer screening), or where there is value in having forewarning (e.g. reproductive implications). When undertaking genetic testing of parents and children together (eg a trio exome or genome), it is also possible that the lab can detect that the family relationships are not as expected, for example, where the father is not the biological father, or that the parents are close relatives.

another challenge is that we all carry variants inc 60 de novo (ie parents didn’t have) 1-2 of which will be in coding region, but if this doesn’t contribute to disease phenotype is an erroneous result
also one disorder can be caused by many genes eg noonan syndrome (11 genes) and one gene can mutate and cause many different disorders

test results are much better if you send a trio (ie both parent’s samples + kids sample, allows interpretation of de novo change etc; send an EDTA bottle and a green top for each person)

Question 11

exome sequencing - picks up mutations in which area, 4 steps

Answer 11

picks up mutations in DNA coding for proteins (not regulatory stuff); genomic DNA cleaved into ~500bp fragments, PCR and library then hybridise with exon probes on library DNA, elute what they bind to and PCR to make exome library, sequence and analyse for mutations; recent national project for families with developmental disorders

Question 12

meiosis - what is the process, what do you end up with; 7 steps in meiosis 1, 5 steps in meiosis 2; what is aneuploidy and why does it occur; 2 ways to classify translocations; what is anaphase lag

Answer 12

Meiosis describes the process of cell division by which gametes are made. In this process, we begin with a cell with double the normal amount of DNA, and end up with 4 non-identical haploid daughter gametes after two divisions.

In meiosis I, homologous chromosomes are separated into two cells such that there is one chromosome (consisting of two chromatids) per chromosome pair in each daughter cell, i.e. two chromosomes total.

Prior to prophase, chromosomes replicate to form sister chromatids. There are initially four chromatids (c) and two chromosomes (n) for each of the 23 chromosome pairs (4c, 2n). The nuclear envelope disintegrates and the chromosomes begin to condense. Spindle fibres appear which are important for the successful division of the chromosomes.

To further increase genetic diversity, homologous chromosomes exchange small parts of themselves, such that one chromosome contains both maternal and paternal DNA. This process is known as crossing over, and the points at which this occurs on a chromosome are referred to as chiasmata.

Prometaphase I
Spindle fibres attach to the chromosomes at points along the chromosomes called centromeres. While this is happening, the chromosomes continue to condense.

Maternal and paternal versions of the same chromosome (homologous chromosomes) align along the equator of the cell. A process called independent assortment occurs – this is when maternal and paternal chromosomes line up and randomly align themselves on either side of the equator. This in turn determines which gamete chromosomes are allocated to, which leads to genetic diversity among offspring.

Anaphase I
Here, each of the homologous chromosomes is pulled towards opposite poles of the cell as the spindle fibres retract. This equally divides the DNA between the two cells which will be formed.

Telophase I and Cytokinesis I
During telophase I, the nuclear envelope reforms and spindle fibres disappear. In cytokinesis I, the cytoplasm and cell divide resulting in two cells that are technically haploid – there is one chromosome and two chromatids for each chromosome (2c, n).

Meiosis II
Prophase II and Prometaphase II
These stages are identical to their counterparts in meiosis I.

Metaphase II
In metaphase II, chromosomes line up in single file along the equator of the cell. This is in contrast to metaphase I, where chromosomes line up in homologous pairs.

Anaphase II
Next, sister chromatids are pulled to opposite poles of the equator.

Telophase II
This stage is the same as telophase I.

Cytokinesis II
Again, the cytoplasm and cell divide producing 2 non-identical haploid daughter cells. As this is happening in both cells produced by meiosis I, the net product is 4 non-identical haploid daughter cells, each containing one chromosome consisting of one chromatid (1c, 1n). These are fully formed gametes.

Abnormalities in chromosome number include aneuploidy, where there is loss or gain of a whole chromosome. This is often due to nondisjunction where there is failed separation of chromosomes during anaphase, so either whole chromosomes (error occurring in meiosis I) or chromatids (error occurring in meiosis II) move to the same pole of the cell. This leaves one gamete short of some genetic information, and the other with additional genetic information.

Abnormalities in chromosome structure are often due to translocations, where there is an exchange of material between two chromosomes, resulting in an abnormal rearrangement. If there is no gain or loss of genetic material, this is a balanced translocation, however, if the exchange of chromosomal material results in extra or missing genes in a daughter cell, it is known as unbalanced and can have clinical effects.

There are two types of chromosomal translocation. Reciprocal translocations take place when the chromosomes break within the arms of the chromosome and Robertsonian translocations take place when whole chromosomes join end to end.

Anaphase lag can occur when chromosomes are left behind due to defects in the spindle fibres or attachment to chromosomes. This differs from non-disjunction as neither cell receives the chromosome/chromatid, leaving both daughter cells short of genetic information.

Question 13

chromosome aberrations - 2 main types, high aneuploidy incidence in what kind of cr, 2 ways embryo can survive this, commonest compatible with life inc 3 different sources, what is non-disjunction and what does it give; commonest reason for ts21, spont abortion and cr aberrations

Answer 13

numerical or structural, high aneuploidy incidence in sex chromosomes, embryo can only survive if on small chromosomes (like 21) or mosaicism

down syndrome most common compatible with life, 90% maternally inherited, 4% paternally and rest post fertilisation giving mosaicism, possible to have extra part of c21 due to translocation

non-disjunction (failure of homologues to segregate) can give aneuploidy (primary in meiosis 1, secondary in meiosis 2)

ts21 usually primary non-disjunction with increased risk with mother’s age

missing or extra chromosomes is most common cause of spontaneous abortion (>50%), esp in first trimester, can be recurrent

Question 14

polyploidy - what percent of embryos triploid, commonest cause, another cause; tetraploidy cause, what cells are naturaly polyploid

Answer 14

3% pregnancies have triploid embryo, incompatible with life: dispermy is cause 66% of time, can also be whole genome non-disjunction in sperm or ovum; tetraploidy rarer, always lethal, due to failure to complete first zygotic division (DNA replicated but no cell division - endomitosis)

some cells (trophoblast in placenta) naturally polyploid

Question 15

translocation mutations - how do they arise, 2 subtypes (amount of material), 2 subtypes (structure), 2 common clinical examples

Answer 15

structural aberration with recombination between non-homologous chromosomes: can be balanced, with no loss or gain of genes and so clinically normal (though increased risk of unbalanced offspring), or unbalanced with loss or gain of genes

can be reciprocal (normal unwanted recombination) or robertsonian with break near centromere of 2 acrocentrics fusing to make a large metacentric and small chromosome which is lost as it has no centromere

95% patients with chronic myelogenous leukaemia have translocation between chromosome 9 and 22 t(9;22)(q34;q11) such that breakpoint cluster region from 22 fused with ABL proto-oncogene of 9 so novel protein (a tyrosine kinase) is generated; balanced translocation of chromosome 21 can give Down syndrome not associated with maternal age

Question 16

copy number variations - 2 main types, clinical example of this; inversion 2 main types and risk

Answer 16

CNVs include duplications and deletions due to unequal recombination with chromosome segment duplicated or missing; digeorge syndrome (22q11.2) is deletion of part of c22 affecting 1:4000 births

2 breaks can cause 180 degree inversion of segment - paracentric if on one arm and pericentric if involving centromere - usually without clinical abnormality but increased risk of generating unbalanced gametes

Question 17

X linked inheritance - what cr males and females get from parents and how this links to XL inheritance x3; sex cr non-disjunction syndromes x3; x-linked recessive conditions x3; how to tell if woman is obligate carrier x2; XL dominant pedigree apperance, 2 clinical egs (inc why girls survive the second)

Answer 17

each son must get Y from dad and one of mum’s X’s, each daughter must get dad’s X

males always manifest recessive X-linked, females might not, and no male to male transmission; if dominant X-linked might be fatal to men, all daughters of affected male will have

sex chromosome non-disjunction can give aneuploidies: 1:5000 turner’s syndrome is XO female with webbed neck, short stature, infertile; klinefelters is 1:1000 XXY male, tall and thin with cancer risk, mild learning impairment and infertile; XYY male 1:1000 clinically normal, increased growth, normal testosterone levels and fertility

515 x-linked recessive traits, variable frequency in ethnic groups, red-green colour blindness, always from father to daughter who is usually carrier if mum unaffected so might skip generation; duchenne’s muscular dystrophy with mutation in dystrophin gene start ~age 6 1:3600, progressive muscle weakness and death in twenties with no known cure; haemophilia: a is factor VIII 1:5000, b is factor IX 1:25,000 obligate carrier if daughter of affected father or mother if: has more than one son with condition or one son and one other blood relative

for dom: pedigree resembles autosomal dominant but no male to male transmission; vit D resistant ricketts, Rett syndrome is early lethal so no affected males, 1 in 8000-10,000 girls (survive due to x inactivation, which also means hetero may not be affected) gives seizures, hard to walk, can’t talk

Question 18

the y chromosome (in general how many gees, what region shared with X, what region determines male sex and what if point mutation or tranlocation of this region; X inactivation why, how determined, 2x consequences, what suggests epigenetic mechanism, what triggers inactivation and what area escapes this x2; what particular epigenetic modification common on activated and inactivated X cr

Answer 18

y chromosome: highly heterochromatic and repetitive with multiple inverted palindromic repeats and gene poor (1% of diploid genome: 60 genes coding for proteins) 2 small regions (psuedoautosomal regions) shared with x that can recombine; SRY gene mapped to smallest bit of Y known to cause maleness, point mutation in it causes XY females and translocation causes XX males; turned female mice into males when injected; SRY initiates testis development

x inactivation: occurs early in placental mammals so not twice amount of gene products; all but one X inactivated, which one is random (could be maternal or paternal) and the condensed one is genetically inactive: consequences of inactivation include patches of hair colour and diluting mutation effects, and a heritable memory of which was inactivated suggests epigenetic mechanism; Xist is non coding RNA that is expressed from the chromosome to be inactivated and initiates inactivation by triggering a hierarchy of epigenetic modifications to condense and heterochromatise the chromosome to repress transcription; pseudoautosomal regions (PAR1/2) at tips of X and Y escape inactivation, can be haploinsufficient; non-PAR genes can also escape inactivation (20% in humans, some of functional Y homologues); histone acetylation strongly present on active X, inactive X undergoes methylation late in inactivation

Question 19

epigenetics - study of what, how can we tell its heritable, 4 ways histones modified and effect on chromatin (which type is actibe and which inactive), how often does epigentic reprogramming occur and at which stages of dev, what are parental imprints resistant to

Answer 19

study of modification to DNA/chromatin and influence on genome function, both local and long range; maintained during division and thus heritable

histone proteins chemically modified inc activating methylation, acetylation, and deactivating methylation (commonest), deacetylation to open or condense chromatin respectively; inactive thus heterochromatic and active euchromatic; correct modifications essential for centromere function; epigenetic tags can also be direct methylation etc of DNA

epigenetic reprogramming is genome wide, twice in development with epigenetic marks erased by passive and active mechanisms which are re-established during implantation for gene regulation, and new ones added: 1st in developing germ cells, in prospermatogonia during fetal development/ growing oocyte phase, 2nd immediately after fertilisation, parental imprints resistant to this one

Question 20

genomic imprinting - how many genes have parental imprinting and what form does this take, 2 ways this can lead to disorders and how trait inheritance map looks + eg of gene expressed only from paternal cr, cause of BW syndrome, PW, angelman, what are DMRs and ICRs and how do epimutations interact with ICR to effect imprinting

Answer 20

maternal and paternal chromosomes behave differently as ~1% of genes (~100-200) imprinted, that is to say germline epigenetic modifications silence one copy (say maternal) and other copy thus acts

IGF2 expressed only from paternal chromosome, abnormal imprinting consequently leading to genetic disorders and cancer; DNA methylation is retained as a heritable memory; disorders arise from uniparental disomy (silver-russell syndrome), which can also unmask recessive conditions like CF, and from mutation or epimutation of imprinting controls; trait maps similar to autosomal but sex of parent matters

Beckwith-Wiedemann syndrome is fetal overgrowth, multi-organ hyperplasia and increased incidence of childhood tumors with altered dosage of IGF2 growth factor due to extra paternal chromosome; Prader-Willi syndrome is neurological disorder with weight gain caused by paternally inherited deletion or fault in paternally expressed imprinted gene on cr 15 (paternal copy needed to work as maternal copy is methylated and so silenced), or double maternal inheritance aka uniparental maternal disomy (as both copies will thus be methylated and inactive); Angelman syndrome is neurological/developmental disorder due to loss of maternally expressed genes or (rarely) uniparental paternal disomy in same region of cr15 (opposite problem as P-W but same area)

differently methylated regions DMRs have different methylation pattern compared to similar chromosomes (eg imprinting), not all of them are imprinting control regions ICRs as some established later, but all ICRs are DMRs; many imprinted genes have single ICR to control their expression and if epimutation causes ICR to lose methylation then normal imprinting is stopped

Question 21

SNPs and haplotypes - how many BPs per SNP, where is most variation, what is a haplotype, how does GWAS work to associate SNPs with phenotypes; difference between SNP and somatic mutation x2

Answer 21

4% difference between us and chimps, 0.1-0.5% difference between individuals; so one single nt polymorphism every 500-1000bp but only 1.5-2% of genome protein coding, most variation outside genes; variants helpful in DNA sequencing when you look at locus where multiple alleles known to occur, these single nucleotide polymorphisms inherited in blocks called haplotypes; genome wide association studies use micro-arrays of SNP variants to case and controls to identify SNPs with high degree of association with a certain phenotype

For example, at a specific base position in the human genome, the G nucleotide may appear in most individuals, but in a minority of individuals, the position is occupied by an A. This means that there is a SNP at this specific position, and the two possible nucleotide variations – G or A – are said to be the alleles for this specific position; SNPs are in the germline and some ppl think they must be present in >1% of population to count, so this is different from a point mutation acquired during life which would be a somatic mutation

Question 22

nondisjunction and link to maternal age - what non-disjunction is, what this results in; why is this more likely with increasing maternal age and link to ts21

Answer 22

homologous chromosomes fail to segregate in meiosis i, sister chromatids in meiosis 2 or mitosis; uniparental disomy with both copies of chromosome from one parent, trisomy and monosomy; mature oocytes believed to have limited capacity for reloading cohesin and cohesin may be lost over time leading to incorrect microtubule kinetochore attachment and chromosome segregation errors, hence increased risk of down syndrome with age

Question 23

DNA replication - initiating move, what are replication forks, leading vs lagging strand, direction of movement in each; 4 main polymerases, role of each; exonuclease activity of first type; second in complex with what trimer which is loaded by what and displaces what in what process; 5 steps ( last just for lagging strand, also which polymerase more on which strand)

Answer 23

nucleophillic attack of 3’-OH on alpha phosphate moiety of incoming dNTP with subsequent PPi hydrolysis driving the reversible reaction; occurs at replication forks which procede bidirectionally; semidiscontinous as okazaki showed by pulse labelling with radioactive thymine, leading strand continuous 5’ to 3’ and lagging strand discontinous fragments, each individually 5’ to 3’ with overall 3’ to 5’ movement

polymerases: alpha, delta, gamma and epsilon, all members of B family based on sequence homology (gamma is family A); alpha extends primer by 20nts then delta takes over on leading and lagging strands with processivity dependent on the PCNA DNA clamp; pol E also does leading strand and isnt dependent on PCNA; gamma is a family which replicates mitochondrial genome

alpha has no exonuclease activity and involved in extending primer so if it makes mistakes bases may be removed with primer anyway; delta in complex with PCNA trimer (proliferating cell nuclear antigen) sliding clamp which is a ring and is loaded by replication factor C RFC (1 large subunit and 4 small) and displaces pol alpha to allow delta to bind in template switching

topoisomerase unwinds, helicase breaks h bonds, DNA primase adds rna primer, then polymerase on leading and lagging strands (more epsilon on former and delta on latter), with latter having okazaki fragments stitched together by ligase

Question 24

physical organisation of the genome - euchromatin is what, 3 charcteristics of where it is, replicated when and how much recombination; heterochromatin is what, x2 where, replicated when and how much recombination; link to x cr

Answer 24

euchromatin is less condensed, in chromosome arms, unique sequences, gene-rich, replicated throughout S phase and undergoes recombination in mitosis; heterochromatin highly condensed, centromeres and telomeres mainly, repetitive sequences, gene poor, replicated late in S phase with less recombination; dosage compensation of x to heterochromatin in females

Question 25

structure of the human genome - 7 regions, what percent codes for proteins and what percent is gene footprint (inc 3 things), what are short tandem repeats (+how much of DNA are these, how big can they get, how do they arise, used in what), segmental duplications are how much of genome; what percent derived from transposons (inc 4 types, how they move, what this facilitates), mini and microsatellites inc why non-trinucleotide repeat expansion matched and triplet in Huntingtons and fragile X

Answer 25

sequences include centromeres and telomeres (latter a form of minisatellite DNA), origins of replication, matrix attachment regions (where DNA attaches to nuclear matrix), protein coding genes (enhancers - oft thousands of base pairs upstream of transcription, promoters - usually <200 base pairs upstream and containing TATA boxes and initiator, exons (each consisting of coding region and 5' and 3' untranslated regions that serve roles like mRNA transport, translation initiation, and attachment of polyA tail), introns (never translated bits between exons, some of which serve as miRNA (post-transcriptional regulation of gene expression etc); rna coding regions (rRNA, tRNA, other miRNAs and misc others) then there are the repeated sequences of which there are satellites and interspersed sequences; former unique sequences repeated in one area that are either minisats (30-35bps) or microsats (2-5bps); some microsats are in coding regions and expansion of these trinuc repeats can cause disease(polyQ diseases, fragile X etc), but most are not in coding regions; latter are sequences which are dispersed across genome rather than in one area and may be short (13% of genome) or long (21% of genome); LINEs and SINEs are both retrotransposons (derived from RNA); besides LINEs and SINEs retrotransposons also inc endogenous retroviruses and the 3 together are >45% of genome big compared to prokaryotes and less gene dense, genes interrupted with introns and lots of repetitive DNA; 2% genome coding for proteins, 25% gene footprint (promoters, exons, introns); some is heterochromatin eg centromeres; 3% of DNA short tandem repeats STRs eg CACA, TATATA arising from template slippage during replication and up to ~100bp, vary between individuals and used in DNA fingerprinting; segmental duplication of 10-300kB ~5% genome, also non-coding RNAs such as miRNAs contains transposons: 45% of euchromatic genome in 100 to several thousand bp are transposon derived repeats, remnants of retrotransposons and most lost ability to mobilise: long interspersed nuclear elements (most inactive due to random mutations accumulated through generations, though some inserted into gene cause disease) short interspersed nuclear elements (parasitic DNA), retrotransposons with large terminal repeats, inactive copies of partially retrotransposed genes; these mobile genetic elements mean genome undergoing constant change as though many inactive some can move around the genome: DNA transposons moved by DNA transposase and retrotransposons DNA to RNA to DNA and inserted elsewhere in genome, facilitate appearance of new genes/patterns of gene expression so evolution and satellite DNA: minisatellites tracts of repetitive DNA in eg telomeres/centromeres, microsatellites smaller (2,3 or 4 nts) unstable microsatellites may undergo trinucleotide repeat expansion which shows genetic anticipation (severity increases with generation number eg Huntingtons due to addition of CAG repeats), non-trinucleotide repeat expansion masked as causes frameshift leading to developmental lethality; CGG expansion within gene on x chromosome gives fragile X syndrome with intellectual disability

Question 26

methods of DNA repair - stingle strand breaks (3), double strand breaks (2)

Answer 26

single strand breaks: base excision, nucleotide excision, mismatch repair double strand breaks: non-homologous end joining, homologous recombination

Question 27

digeorge syndrome - aka, genetic cause leading to defect where and how does this lead to impact on immunity, mnemonic for remembering features

Answer 27

DiGeorge syndrome, also called 22q11.2 deletion syndrome, results from a microdeletion in a portion of chromosome 22 that leads to a developmental defect in the third pharyngeal pouch and third branchial arch. consequences include incomplete development of parathyroid glands and the thymus gland. An underdeveloped thymus gland results in an inability to create functional T cells. Features of DiGeorge syndrome can be remembered with the CATCH-22 mnemonic: C – Congenital heart disease (conotruncal eg VSD) A – Abnormal faces (characteristic facial appearance inc hypertelorism, low set ears, cleft palate) T – Thymus gland incompletely developed C – Cleft palate H – Hypoparathyroidism and resulting Hypocalcaemia 22nd chromosome affected

Question 28

klinefelters - appear as normal which gender until when, then develop what 9 features (which aspects of learning x2 esp affected), what improves many sx, what can potentially allow fertility, 2 more mx

Answer 28

Usually patients with Kleinfelter syndrome appear as normal males until puberty. At puberty can develop features suggestive of the condition: Taller height Wider hips Gynaecomastia Weaker muscles Small testicles Reduced libido Shyness Infertility Subtle learning difficulties (particularly affecting speech and language) finding of hypergonadotropic hypogonadism indicates primary gonadal failure: FSH elevation typically predominates over LH, though both are elevated above normal. Testosterone concentrations are usually low or low-normal in both adolescents and adults. Sex hormone-binding globulin (SHBG) tends to be elevated, which causes the free testosterone in the serum to be disproportionately low compared to the total testosterone. The majority of adults with KS will have hypogonadism, but not all. Serum estradiol is high-normal or elevated, but the estradiol/testosterone ratio is consistently elevated, which may explain the gynecomastia Testosterone injections improve many of the symptoms Advanced IVF techniques have the potential to allow fertility Breast reduction surgery for cosmetic purposes MDT input

Question 29

klinefelter syndrome - genetic problem, frequency, apperance (5), genitals (4), intelligence (2)

Answer 29

47 XXY 1:1000 males signs minimal before puberty; tall w long limbs, thin and feminine body shape, gynaecomastia in 40%, small/firm testes, small penis, maybe cryptorchidism, infertile, normal intelligence usually, may have problems in using/perceiving spolen language,

Question 30

noonans - 9 appearance, 6 associated conditions (inc 3 eg for first condition)

Answer 30

Short stature Broad forehead Downward sloping eyes with ptosis Hypertelorism (wide space between the eyes) Prominent nasolabial folds/upturned nose Low set ears Webbed neck Widely spaced nipples Associated Conditions Congenital heart disease, particularly pulmonary valve stenosis, hypertrophic cardiomyopathy and ASD Cryptorchidism (undescended testes) can lead to infertility. Fertility is normal in women. Learning disability Bleeding disorders Lymphoedema Increased risk of leukaemia and neuroblastoma

Question 31

noonan syndrome - inheritance, which gene/cr, karyotype, gender ratio, looks like what other condition and implication; stature, 4 facial features, common valve disease

Answer 31

AD, missense mutations in the PTPN11 gene on chromosome 12, normal karyotype, 1:1 M:F phenotypically like turner syndrome, so if male and looks like turner think noonan short stature, traingular facies, hypertelorism, epicanthic folds, thin upper lip, pulm stenosis

Question 32

prader-willi (caused by loss of what/where, main rx strat), angelmans (4 features + 4 appearance)

Answer 32

Prader-Willi Syndrome is a genetic condition caused by the loss of functional genes on the proximal arm of the chromosome 15 inherited from the father. Growth hormone is indicated by NICE as a treatment for Prader-Willi Syndrome, aimed at improving muscle development and body composition Angelmans: Delayed development and learning disability Severe delay or absence of speech development Coordination and balance problems (ataxia) Fascination with water Happy demeanour fair skin/light hair/blue eyes/widely spaced teeth

Question 33

genetics of angelman and prader-willi syndrome - what class of disorder, where is the problem, 2 ways to get for each

Answer 33

imprinting disorders due to del 15q11-13 - angelman syndrome if maternally derived deletion and prader-willi if paternally derived deletion; also if uniparental disomy with both cr15 from mum then prader willi and from dad then angelman, thus seems it is lack of normal mums resulting in angelmans and normal dads resulting in prader willi; this is half of cases, remainder due to other genetic abnormalities

Question 34

angelmans - 6 appearance, 2 behaviour, 4 neurologic; prader willi - fetal growth, 4 appearance, 4 other features, problem later in life, 2mx

Answer 34

angelmans - microceph w brachyceph, fair hair/blue eyes, large tongue, prominent jaw, mental retardation, easily provoked paroxysms of laughter, seizures esp salaam attacks, slow wave cycles of 4-6s on eeg, hypotonic, stiff-legged broad based ataxic gait pw - IUGR, short stature, almond eyes, long silky hair, small mouth w downturned corners, hypotonia, mental retardation, hypogonad, feeding problems from birth so initially small then pathological appetite at 2-3yo leading to obesity, later in life DM and cardiac disease - need strict dieting and lifestyle changes, GH can help with short stature; prone to temper tantrums

Question 35

essential genetic pedigree knowledge (M vs F, affected vs carrier, arrow points to who, how to indicate deceased, twins (mono vs dizygotic); 2 carrier parents chance of affected, carrier, normal; consanguinous families and AR incidence, 5 egs, sex ratio for AR; AD parent % kids affected, mutation rate compared to AR, sex ratio, 6 egs; XLR sex ratio, offspring affect or carrir M vs F; XLD offspring pattern for affected M vs F, 2 egs; how to interpret likely pattern based on sex ratio (3), likely pattern if affected male beget affected male

Answer 35

male square, female circle; coloured in if affected, half coloured if recessive carrier arrow points to the proband diagonal line for deceased diagonal line to two shapes means twins, if the shapes joined by a single line then monozygotic and if not dizygotic AR has carrier parents, this couple would have 50% carrier, 25% affected, 25% normal consanguinous families increase chances of AR conditions; M:F ratio 1:1; egs ae CF, sickle cell, beta thalasaemia, SMA, inborn errors of metabolism AD: inherited from affected parent, half kids affacted and half normal, high spontaneous mutation rate compared to AR conditions, M:F ratio 1:1, greater variation in expression, eg hereditary spherocytosis, myotonic dystrophy, retinoblastoma, tub scler, friedreich ataxia, polycystic kidneys x-linked recessive: males affected, but females may show features (eg prolonged clotting time in haemophilia or raised CPK in duchenne) due to x-inactivation; female carrier has half males affected and half females carriers, affected male has all male normal and half females carriers x-linked dominant: affected fathers have normal sons and affected daughters, affected females pass to half their offsrping; often lethal to males so only females born; eg x-linked hypophosphataemic rickets, incontinentia pigmenti if M:F ratio 1:1 likely AR/AD; if females more think x linked dom, if no females affected think x linked recessive; affected male beget affected male means AD likely - large pedigree may be needed to prove this vs x linked dom

Question 36

A couple come for genetic counselling about the risk that their child will have cystic fibrosis. The husband's sister has it, but the husband is not affected and there is no history in the wife's family of the disease. Give answer as fraction

Answer 36

population rate 1 in 25 so assume wife has 1 in 25 chance of carrying husbands parents must both be carriers, as he doesn't have it then he must either be AA, Aa, or aA therefore 2/3 chance he is carrier if both parents carries then chance of child being affected is 1/4 so answer is 1/25 * 2/3 * 1/4 = 2/300

Question 37

chromosome analysis (number of pairs, how sorted in karyotype x3 factors with two things changing as move left to right, genetic test procedure (usually use what cell, what phase is cr arrested in for staining), general approach to analysing a karyotype (look for 3 things first), how to describe a chromosome pattern formally (3 things and eg for normal turner, klinefelter, cri du chat, how translocations are described)

Answer 37

23 pairs - 22 autosomes and one sex sorted by size, positionof centromere, and banding pattern with top left side being large chromosomes with median placed centromeres - then left to right become smaller and centromere more distal to form acrocentric chromosomes genetic testing most convenient with peripheral blood lymphocytes but almost any tissue can be used; arrest chromosomes in metaphase and stain them look to see if missing a sex chromosome, has extra sex chromosomes, or has an extra autosome to describe a chromosome pattern say total number, sex chromosome composition, then genetic abnorm eg normal is 46 XX, turner is 45 XO, klinefelter 47 XXY, cri du chat 46 XY, del (p5) translocations are expressed as t(a;b)(p00;q00) where a and b are the numbers of the chromosomes involved and 00 are the break points

Question 38

inheritance of down syndrome (risk at diff ages, most common cause, second-most common including what a parent may have (what their cr makeup is) and how that impacts risk in M vs F, third cause, AFP (checked when, 4 reasons high, 1 low; triple test uses what 2 other things and are they high or low; detection and false positive rate

Answer 38

risk is 1:2000 if mum 20yo, 1:700 if 30yo, 1:100 at 40 and 1:50 at 45yo cause almost always (95%) non-disjunction during first meiotic division resulting in extra cr21, with 88% due to non-disjunction of maternal gamete and 8% non-disjunction of paternal gamete; in 2-3% of cases is instead a translocation a robertsonian translocation is where long arms of two acrocentric cr fuse at the centromere, giving 45 chromosomes but unaltered ('balanced') genetic makeup so normal phenotype; however may have cr unbalanced offspring due to inheriting the extra long arm - it may either be attached to another cr, commonly cr 14, or to another version of itself (XXt21;21) giving an isochromosome isochromosome - unbalanced structural abnormality in which the arms of the chromosome are mirror images of each other, so eg consists of f two copies of either the long (q) arm or the short (p) arm giving partial trisomy of the duplicated genes and partial monosomy of the deleted ones in a child with unbalanced translocation causing down syndrome there is a 25% risk parent has balanced robertsonian translocation (commonly 45 XXt(21;14), with remaining 75% of the time it being de novo; hence if baby born with down syndrome due to translocation need to karyotype both parents if the parent is carrying a balanced robertsonian translocation they have 1:4 chance of forming a down syndrome zygote, but also 1:4 chance of forming monosomic 21 zygote (as gets nothing from affected parent) which aborts, so risk of fetus carrying falls to 1:3 and many of these babies abort naturally meaning risk in carrier mother is actually 1:10, 2% risk if father (as sperm immotility results) in 1% of cases down syndrome due to mosaicism, these children have milder phenotype; this is either due to a nondisjunction event during an early cell division leads to a fraction of the cells with trisomy 21 or when an anaphase lag of a chromosome 21 in a Down syndrome embryo leads to a fraction of euploid cells maternal serum AFP taken at 16-18 weeks - high if NTDs, abdo wall defects, multiple pregnancies, intrauterine death; low in down syndrome; triple test also uses hCG (high) and unconjugated oestriol (low); 60% detection rate with 5% false positives

Question 39

down syndrome antenatal diagnosis

Answer 39

All pregnant women to be offered screening for Down, Edwards and Patau syndromes. combined test can be performed when the baby’s crown rump length (CRL) is between 45.0mm and 84.0mm. This is between 11+2 and 14+1 weeks. The nuchal translucency (NT) measurement is needed to calculate the chance result. The blood sample can be taken from 10 weeks, but normally at the time of the 12 week scan If the NT cannot be measured, or the CRL measurement is greater than 84.0mm, the woman is offered the quadruple test. If accepted, this test can be performed when the baby’s head circumference (HC) is between 101.0mm and 172.0mm. This is between 14+2 and 20+0 weeks. The blood sample can be taken from 14+2 weeks but quadruple test is not as accurate as combined test Women found to be higher chance for any of the syndromes to be offered the options of non-invasive prenatal testing (NIPT) and prenatal diagnosis (aka amniocentesis or CVS) combined test uses maternal age, beta HCG (An increased level of bhCG in maternal blood in the first trimester is associated with Down’s syndrome. Conversely, a decreased level is associated with Edwards’ and Patau’s syndrome), PAPP-A (decreased level of PAPP-A in maternal blood in the first trimester is associated with Down’s syndrome (trisomy 21), Edwards’ syndrome (trisomy 18) and Patau’s syndrome (trisomy 13)), nuchal thickness and crown rump length quadruple test only looks for down syndrome and looks at maternal age as well as for low AFP and unconjugated oestriol and high bHCG and inhibin A chance cut off of 1 in 150 then applied, lower risk if < 1 in 150 and higher risk if > 1 in 150 NIPT assesses placental cell-free fetal DNA found in maternal blood and combines this with the mother’s background probability of a trisomy (mother’s age or the combined test results offered within the NHS) to obtain a likelihood ratio to predict whether or not the baby is more likely to have a chromosomal condition, to inform whether to proceed to diagnostic testing CVS takes sample from placenta and is indicated at 11-14 weeks gestation and amniocentesis taking amniotic fluid >15 weeks; uncomfortable, 1 in 200 risk of miscarriage and 1 in 1000 risk of serious infection; normally obtained DNA sent for full karyotype and takes 2 weeks for these results to come back, fast-FISH can be done and get result in matter of days but only available privately note can apply combined test separately to each baby in a pregnancy if dichorionic or provide one overall probability if monochorionic

Question 40

down syndrome - number of births, height, IQ, 3 skull features, 3 eye features, 5 face features, 7 associated congenital conditions (inc ix needed before contact sports and 3 sx to beware), 2 neurological features, 5 features of hands/feet, increased risk of 3 conditions, how many die in first 5 years and main cause

Answer 40

1:800 live births short, IQ oft <50, dev delat brachycephaly, third fontanelle, delayed font closure upward slanting palpebral fisures, epicanthic folds, cataracts upturned nose, small ears, inc'd middle ear infections, downturned mouth, protruding tongue inc'd risk of congen or autoimmune hypothyroid; atlanto-axial intability (beware neck pain, limb weakness, or paraesthesiae and screening x-ray before contact sports) congen heart disease, esp AVSD; tracheo-oesopg atresia, duodenal atresia (double bubble), annular pancreas, hirchsprungs hypotonia, 10% get epilepsy -10x prev of normal pop short/broad hands, single palmar crease, clinodactyly; short broad feet w inc'd space between hallux and 2nd toe increased risk of ALL, AD, rec resp infections from poor white cell function 15-20% die in first 5 years mainly due to CHD, many live into 60s or later

Question 41

postnatal management of down syndrome

Answer 41

review: are they clinicall well? if yes: karyotype and full cr analysis, FBC and film, Pre & Post Ductal saturations, ECG & CXR. Echocardiogram within 6 weeks; chase newborn screen for congen hypothyroidism; Routine newborn hearing screen.Audiology F/U: 8mo. - Routine ophthalmologic examination (during NIPE) and ophthalmology referral on discharge for routine F/U - Ensure Baby has opened bowels/passed urine - Plot growth on the DS growth chart -assess feeding, if poor then admit to neonatal unit, if satisfactory then discharge planning with neonatology clinic follow up and referral to community paediatric team if clinically unwell are you worried about congen heart disease, duodenal atresia/bilious vomiting, poor feeding, resp distress, or re/post-ductal sat difference >3% CV Between 40 and 60% of babies with Down syndrome have congenital heart defects. Of these 30 - 40% are complete atrioventricular septal defects (AVSD). Most AVSD can be successfully treated if the diagnosis is made early and the baby referred for full corrective surgery before irreversible pulmonary vascular disease (PVD) is established. Haem DCC performed but limited to 1 minute; All babies with suspected or confirmed Down syndrome should have a FBC and a Blood film taken in the first 2-3 days of life, ideally at the same time as their genetic tests as Transient Abnormal Myelopoiesis (TAM) is a congenital leukaemia unique to neonates with Down syndrome or mosaic trisomy 21 - Any neonate with a blast percentage of >10% and/or clinical features suggestive of TAM (bruises, bleeding easily, liver & Renal impairment, infection) should be discussed urgently with the regional paediatric haematology centre and blood sent for GATA1 genetic testing Sensation OME present at birth in 35% of babies with TS21 and tenfold higher incidence of congenital cataract and infantile glaucoma

Question 42

health assessment for child with down syndrome

Answer 42

Babies with DS should have neonatal screening undertaken prior to discharge as in other flashcard they will then be followed up regularly in the community including full history of any respiratory, cardiac, or bowel symptoms and any concerns about vision and hearing, plus checking if any issues with sleep, plotting growth, and performing developmental assessment, plus from age 1 looking for evidence of cervical spine instability, middle ear disease, squint, cataract, nystagmus, nasolacrimal duct obstruction, blepharitis, and as child becomes older considering need for contraception (adolescent); careful auscultation of heart also indicated complications to be aware of: 40% have CHD, AVSD commonest; duodenal atresia, hirschprungs disease, short stature, AML (normally between 1 and 5 yo, most commonly 2 yo) and ALL (more likely than AML after 3 and most cases by 6yo), 10% of DS kids will have some form of myeloproliferative disorder like temporary leukaemia that resolve within 3 mo 8% will have epilepsy with common patterns inc focal, infantile spasms, and GTCS global dev delay with challenges in the expressive language domain compared with receptive language. IQ can range from mild to moderate intellectual disability, between 40 and 72 30-60% get OSA (recommended all children get sleep study between 3 and 4yo) hearing loss, increased susceptibility to URTIs - if hospital admission, recurrent other infections, or infections severe may need immunodef screening and some areas will do basic immunodef screening for all DS patients hypothyroidism in up to 20%, nasolacrimal duct obstruction due to midface hypoplasia, congenital cataracts, strabismus, delayed primary and secondary dentition and small mouth leading to crowding; coeliac disease in 7-16%, high incidence of seb derm and up to 9% have alopecia areata ligamentous laxity and low muscle tone may contribute to knee and hip problems, and increase susceptibility to subluxation and dislocations ASD and ADHD may be seen; depression and dementia (in 50s) both as adults About 15% of patients have lax atlanto-axial joint. This may result in spinal cord compression in 1% to 2% of cases.In terms of atlanto-axial subluxation, symptoms of myelopathy should be sought, including neck pain, changes in head positioning or torticollis, spasticity or change in tone, radiculopathy, incontinence, changes to gait (inc worsening mobility or frequent falls), or hyper-reflexia

Question 43

genetics of cystic fibrosis - gene location, name and how many mutations result in disease, commonest mutation

Answer 43

chromosome 7q (long arm) encoding CFTR; large gene and >200 different mutations result in disease, commonest being three base pair deletion resulting in deletion of one phenylalanine in position delta F508 (70% of ppl overall in europe/north america)

Question 44

genetics of duchenne muscular dystrophy - how big, what % of what cr, protein encoded for, spontaneous mutation how often, otherwise what inheritance pattern; implication of x-inactivation

Answer 44

large gene, being 1% of the X cr, encoding the protein dystrophin and deficiency of this results in the disease spontaneous mutation in 1/3 of cases, otherwise XLR; males affected, females not bu x-inactivation means some muscle cells may release CPK

Question 45

genetics of fragile X syndrome - how common, what is the fragile X gene (rpt type, which cr), condition shows what phenomenon

Answer 45

most common inhertiable type of mental retardation in males, 30% of cases; also 10% of mild cases in females; fragile X gene is an overamplified section of DNA in the X cr with variable numbers of CGG repeats this condition shows anticipation, as does huntingtons and myotonic dystrophy

Question 46

fragile x syndrome - incidence, commonst cause of what, how common relative to other cr problems, 8 features, when do features appear, what ix to send and when

Answer 46

1:1000, inferited, commonest cause of mental retardation worldwide (30% of boysand 10% of mild in girls), 2nd most common cr problem after ts21 macroceph, large ears/jaw, prominent forehead, high-arched palate hyperextensible joints, flat feet, mitral valve prolapse macro-orchidism most of these features may not present before puberty so if investigating cause of mental retardation send off chromosomal analysis looking for fragile sites on x cr

Question 47

patau and edward syndromes - what trisomy respectively, patau (13 features), edward (14 features), prognosis x2

Answer 47

ts13 and ts18 ts13 - IUGR, cutis aplasia commonly over vertex, microceph, cataracts/colobomata, microphthalmia, holoprosencephaly, low set ears, cleft lip/palate, congen heart disease in 80% (ASD, VSD, PDA), polydactylyl, hypoplastic nails, clinodactylyl, renal and ext genitalia problems ts18 - microceph, prominent occiput, micognathia, narrow forehead, cleft lip/palate, low-set ears, congen heart disease, short sternum, clenched hands w overlapping fingers, clinodactylyl and hypoplastic nails, rockerbottom feet due to vertical talus, kidney problems, apnoea prognosis for both - 60% dead in first 2 days, 90% in first year

Question 48

turner syndrome - incidence, 3 ways possibly picked up prenatally, 2 ways at birth, 15 features (inc something to trigger you to karyotype a female)

Answer 48

1:2500 may be picked up in utero as generalised oedema or cystic collections like hygroma (can give polyhydramnios if not swallowing) or pleural/pericard effusions at birth: carpal or pedal oedema + hypoplastic nails over time short stature, low-average intellect (10% retardation), secretory OM, low hairlines, webbed neck, widely spaced hypoplastic nipples, cubits valgus, 20% congen heart disease (mainly bicuspid aortic valve or coarctation of aorta - this abnorm 3x more common in males normally so if female has worth getting a karyotype), shield shaped chest, renal abnorms (horseshoe kidney), sexual immaturity due to streak gonads, pigmented naevi, cafe au lait macules, any x-linked conditions that normally boys in family get

Question 49

william syndrome - usual inheritance inc what happens to genes, affected cr, 11 features and diet possibly indicated

Answer 49

sporadic usually, deletion of up to 28 genes on cr 7 mild microceph, mental retardation, elfin facies w short palp fissures, upturned nose, cupid bow upper lip (long philtrum); lively manner, may have failure to thrive, supravalvular aortic stenosis, sometimes pulm sten, 50% have hypercalc which can cause htn then renal famage; child may need low ca low vit D diet

Question 50

fetal alcohol syndrome - what influences severity; 14 features inc what heart problems commonest

Answer 50

varying severity depending on how much alcohol mother drank IUGR, mental retardation, microceph, microphthalmia, short palp fissures, hypertelorism, maxillary hypoplasia, retrognathia, smooth philtrum and thin upper lip, 40% heart defects (ASD,VSD commonest), joint contractures, renal defects, babies may be irritable and child hyperactive

Question 51

waardenburg syndrome - inheritance pattern, 6 features

Answer 51

AD inheritance square face w thin nose, dystopia canthorum (not same as hypertelorism), heterochromia, 80% have sensorineural deafness, white forelock in 30% cases

Question 52

alagille syndrome - common liver problem, 7 other features

Answer 52

hypoplasia of intralob duct giving hepatic cholestasis as neonate or infant, triangular thin face w prominent forehead and small chin, pulm stenosis, butterfly vertebrae, pruritus and xanthomas

Question 53

silver-russell syndrome - aka, inheritance and affected parts, 8 features

Answer 53

note called russell-silver syndrome in usa generally sporadic, multiple mutations cause, oft problem on cr 7 or 11, it is a disorder of imprinting IUGR, short stature aka dwarfism (growth follows lower centiles but doesnt cross), normal intelligence, small triangular face, hemihypertrophy becoming more obvious over time, cafe au lait macules, hypospadias, clinodactyly

Question 54

jeune asphyxiating thoracic dystrophy - inheritance pattern, anatomical problem, general presentation and prognosis

Answer 54

AR w small narrow chest thats immobile so diaphragmatic breathing, rest of body normal baby presents w resp distress and commonly fatal in neonatal period, but milder forms can survive past this point

Question 55

arthogryposis multiplex - related to what, 6 features, 5 features to make you suspect what other syndrome (and why it happens)

Answer 55

related to poor intruterine mobility (maybe due to oligohydramn) many limb contractures w fibrous ankylosis of joints w hips and wrists in flexion (dislocation of hips common), knees and digits flexed and elbows extended, also musc wasting if also pulm hypoplasia, low set ears, micrognathia, beaked nose, wide set eyes consider potter syndrome which has renal agenesis -> oligohyd

Question 56

soto syndrome - aka, 7 features

Answer 56

aka cerebral gigantism macrosomia at birth, excessive growth in first few years (but normal adult weight), large head/hands/feet - esp face looks long, some intellectual retardation, clumsiness and maybe mild vent enlargement

Question 57

moebius syndrome - what it is, why it happens, associated with what x4

Answer 57

congen paralysis, usually bilat, of 6th and 7th CN due to agenesis of related nuclei (likely after vascular insult), associated with strabismus, clubbed feet, missing digits, poland syndrome

Question 58

megalencephaly - what it is due to, 2 normal/absent things

Answer 58

large head from birth due to inc'd brain size, no hydroceph and normal csf may be familial

Question 59

russell diencephalic syndrome - what causes, 7 features, general mx

Answer 59

usually caused by a brain tumor such as a low-grade glioma or astrocytoma located in the hypothalamic-optic chiasmatic region from 6-7mo get severe failure to thrive and cachexia despite normal calorie intake; child usually excitable and wide eyed (due to upper eyelid retraction) hypoglyc, optic atrophy, nystagmus, nutritional support and treat underlyinh lesion

Question 60

pierre-robin syndrome - 4 features, 2 mx for feeding, 3 other additional features suggestive of what syndrome

Answer 60

high arched palate, cleft palate, micrognathia, post displacement of tongue may cause resp obstruction feed with orthodontic teats, get dental plates if also severe myopia (maybe ret detach), cataracts, deafness then stickler syndrome

Question 61

treacher-collins syndrome - inheritance pattern, defect where - gene + structure, 10 features

Answer 61

AD but often sporadic mutation, change in the gene TCOF1 (cr 5) causes up to 93 per cent of cases of Treacher Collins syndrome + 2 other genes identified, first/second branchial arch defect micrognathia, colobomata, zygomatic hypoplasia, low-set ears, deafness, preauricular sinuses and maybe absent ext aud canal, VSD, fused radius/ulna, mental retardation in some

Question 62

klippel-feil syndrome - gender ratio, 7 features

Answer 62

2x common in females cervical verts may fuse giving short stiff neck, low hairline, kyphoscoliosis, sprengel deform, canal stenosis (radiculopathy, myelopathy), 1/3 deaf, syringomyelia/syringobulbia

Question 63

meckel-gruber syndrome - inheritance pattern, what it is, mx + prognosis, 2 ddx

Answer 63

AR triad of occipital encephalocoele (may be covered in hairless skin, usually in midline and large can give neuro deficits), polydactylyl, polycystic kidneys sugical removal of encephs and make baby comfortable, but condition is fatal; may be confused for haemangiomas or cephalhaematomas

Question 64

goldenhar syndrome - defect where, 8 features, mx

Answer 64

due to 1st/2nd branch arch defects giving coloboma, epibulbar dermoids, low seat ears with abnorm pinna or skin tags, deafness, fused cervical verts, renal and cardiac (septal defects) abnorms, may have learning problems or ASD often on one side of body (hemifacial microsomia), may see aplasia/dysplasia of organs on one side mx is surgery to deal with structural issues + glasses/hearing aids etc as needed

Question 65

poland syndrome - inheritance, what it is, 3 features

Answer 65

seems to be acquired w/o a genetic association complete or partial aplasia of sternal head of pec major flattening hemithorax on that side w loss of breast and subcut tissue, inversion of nipple, oft ipsi hand deforms (syndactylyl in 1/3 cases)

Question 66

lowe syndrome - inheritance pattern, 5 features

Answer 66

xlr glaucoma, bilat cataracts, severe mental retardation and hypotonia, fanconi syndrome

Question 67

batten disease - inheritance, term for what, onset when, 5 features, 2 tests, mx approach

Answer 67

AR lysosomal storage disorder (used to refer to all 13 diseases within the neuronal ciroid lipofuscinoses group, which onset at various different ages) juvenile forms often onset 5-10yo giving prog mental retardation and cerebral palsy, blindness w optic atrophy, seizures (various kinds) and death by teenage years, some start earlier or even as an adult electroretinogram diagnosis, high amplitude spikes on EEG mx supportive with AEDs, sx control, nutritional support etc

Question 68

aicardi syndrome - sex ratio, due to what, 9 features

Answer 68

females only (or boys with klinefelters), due to partial or complete absence of corpus callosum mental and dev retardation, infantile spasms, cortical and corpus callosum defects, retinal lacunae (giving impaired vision), choroidoretinitis, colobomata, costovert abnorms (inc extra or missing ribs, vert abnorms giving scoliosis), constipation/diarrhoea/GORD

Question 69

zellweger syndrome - inheritance pattern, what it is, 11 features

Answer 69

AR peroxisomal disorder w congen hypotonia, seizures, mental retardation, midface hypolasia, narrow high forehead, large fontanelles, pigmanteray retinopathy, corneal opacities and cataracts, hepatomeg and cirrhosis, polycystic kidneys

Question 70

CHARGE syndrome caused by, needs how many of which 6 features, acronym stands for

Answer 70

complex genetic disorder at least 4 out of the 6: colobomata, heart defects, atresia of choana, retardation (growth/mental), genitourinary abnorms, ear abnorms (inc deafness) CHARGE syndrome is an acronym for coloboma, heart disease, atresia of the choanae, retarded growth and mental development, genital anomalies, and ear malformations and hearing loss. Mutations in the CHD7 (chromodomain helicase DNA binding protein) gene present on 8q12 in over 90% of kids with this syndrome - can be AD inheritance but usually de novo; mutation gives interupted gene expression and disordered neural crest development, with deficiency in the passage of cervical neural crest cells into the pharyngeal pouches and arches, lack of mesoderm development, and codefective interface between neural crest cells and mesoderm

Question 71

riley-day syndrome - aka, inheritance pattern and commoner where, 11 features, crisis

Answer 71

aka familial dysautonmnia AR, seen mostly in ashkenazi jews failure to thrive, periph neurop giving insens to pain and temp, lack of tendon reflexes, lack of tears so corneal abrasions, mental retardation and poor coordination, hyperpyrex and dehydration due to poor temp control, smooth tongue, excessive sweating and drooling, paroxysms of htn/sweating/blotching + postural drops due to labile BP, rec aspirations (due to GI dysautomnia causing GORD and vomiting, also poor swallowing) may have autonomic crisis in response to physical or emotional stress with vomiting, sweating, hypertension etc

Question 72

rubinstein-taybi syndrome - 6 features

Answer 72

mental and growth retardation broads thumbs/1st toes microceph w max and mand hypoplasia and anteverted nose

Question 73

cornelia de lange syndrome - 14 features

Answer 73

IUGR, mental/growth retardation, confluent bushy eyebrows, long curly eyelashes, low hair line and low set ears, micrognathia, thin lips, small anteverted nose, long smooth philtrum, phocomelia and micromelia w lobster hand, maybe excessive hair on limbs and trunks; ASD or VSD

Question 74

leopard syndrome - what it is, 7 features, mnemonic

Answer 74

a subtype of noonan syndrome lentigines, ecg abnorms (bundle branch block), ocular hypertelorism, pulm stenosis, abnorm genitalia, retarded growth, and deafness named based on an acronym, mnemonic for the major features of this disorder: multiple Lentigines, ECG conduction abnormalities, Ocular hypertelorism, Pulmonic stenosis, Abnormal genitalia, Retardation of growth, and sensorineural Deafness

Question 75

holt-oram syndrome - inheritance pattern, 2 features

Answer 75

AD w thumb/radius/ulna hypoplasia or dyplasia (may also affect eg scapula), ASD/VSD (or conduction abnorms)

Question 76

hereditary telangiectasia - inheritance pattern, 4 common places to find them, link to age, 3 complications

Answer 76

AD multiple telengiectasis anywhere but esp skin, GIT, brain, int organs; size and number inc with age bleeding causes complications like intacereb bleed etc act as AV fistula which can produce cyanosis if right to left shunt or large enough to cause heart failure

Question 77

smith-lemli-opitz syndrome - inheritance, 10 features

Answer 77

AR microceph, hypo then hypertonia, seizures, cryptorchidism and hypospadias in males and hypoplastic labia in femeales, broad upturned nose, ptosis, bitemporal narrowing, micrognathia, low set ears, clenched hand and syndactyly (esp 2nd/3rd toes) or polydactyly; heart/renal/GI abnorms

Question 78

septo-optic dysplasia - 3 features and problems they cause

Answer 78

hypopitu, optic nerve hypoplasia (giving visual problems), absent septum pellucidum (epilepsy, dev delay, cerebral palsy) (2 out of 3 needed, only 30% of patients have all 3)

Question 79

VATER association - 6 features, intelligence

Answer 79

hemivert and sacral defects, anal atresia, tracheo-oesoph fistula, oesop atresia, radial limb and renal hypoplasia, usually normal intelligence but may get VSD and other limb defects in which case might be called VACTERL syndrome

Question 80

thanatophoric dysplasia - how common, what it is, 4 features

Answer 80

v rare but oft in exams lethal condition w babies born stillborn or dying not long after birth have v small chests, fishbone vertebrae and telephone handle femurs on xray, short limbs with folds of excess skin

Question 81

osteogenesis imperfecta, abnormality in what, type 1 (inheritance, 8 features), type 2 (inheritance, 5 features), type 3 (inheritance, 4 features), type 4 (inheritance, 2 features)

Answer 81

abnorm in type 1 collagen form type 1 is AD, short stature, wormian bones on SXR, fragility (diaphysis>meta) giving rec fractures and deform, freq dec after puberty; scoliosis, blue sclerae, conductive deafness in 50%, may have hypoplastic translucent teeth, aortic regurg link type 2 AD/AR, v severe, born with multiple fractures, dark blue-grey sclerae, trianguler face w beaked nose, stillborn or die shortly after birth type 3 AD/AR giving severe osteoporosis w resulting fractures giving shortening and deform of long bones; normal sclerae, abnorm teeth, easy bruising type 4 AD, normal sclerae, fragility varies from mild to mod

Question 82

ellis van creveld syndrome - 7 features

Answer 82

short stature (acromelic dwarfism), polydactyly, brachydact, CHD eg ASD, fine diffusely sparse hair, hypoplastic small nails, hypoplastic or peg/conical teeth

Question 83

conradi syndrome - inheritance, 6 features

Answer 83

XLD inheritance short limbs; scaly/flaky skin, cataracts in 30%; ca stippling of epiphyses, mental retardation can occur; risk of PDA, VSD

Question 84

potter sequence - due to what, 3 groups of features and most common characteristic finding for a common cause, 7 causes; subtypes

Answer 84

atypical physical appearance of a baby due to oligohydramnios experienced when in the uterus includes clubbed feet, pulmonary hypoplasia and cranial anomalies - parrot beak nose, redundant skin, and the most common characteristic of infants with BRA which is a skin fold of tissue extending from the medial canthus across the cheek. The ears are slightly low and pressed against the head making them appear large; may see sirenomelia oligohydramnios can be caused by renal diseases such as bilateral renal agenesis (BRA), atresia of the ureter or urethra causing obstruction of the urinary tract, polycystic or multicystic kidney diseases, renal hypoplasia, amniotic rupture, toxemia, or uteroplacental insufficiency from maternal hypertension classic potters sequence due to BRA; type I ARPKD; type II other forms of renal agenesis; type III ADPKD; type IV obstruction of kidney/ureter; then other

Question 85

bloom syndrome

Answer 85

rare autosomal recessive genetic disorder characterized by short stature, predisposition to the development of cancer, and genomic instability - caused by mutations in the BLM gene which is a member of the RecQ DNA helicase family most prominent feature of Bloom syndrome is proportional small size. The small size is apparent in utero. At birth, neonates exhibit rostral to caudal lengths, head circumferences, and birth weights that are typically below the third percentile; econd most commonly noted feature is a rash on the face that develops early in life as a result of sun exposure. The facial rash appears most prominently on the cheeks, nose, and around the lips it is erythematous and telaniectatic and also develops on other sun exposed areas characteristic facial appearance that includes a long, narrow face; prominent nose, cheeks, and ears; and micrognathism or undersized jaw. There is a moderate immune deficiency, characterized by deficiency in certain immunoglobulin classes and a generalized proliferative defect of B and T cells. The immune deficiency is thought to be the cause of recurrent pneumonia and middle ear infections in persons with the syndrome There are endocrine disturbances, particularly abnormalities of carbohydrate metabolism, insulin resistance and susceptibility to type 2 diabetes, dyslipidemia, and compensated hypothyroidism types of cancer and the anatomic sites at which they develop resemble the cancers that affect persons in the general population but age earlier; many have multiple cancer diagnoses and average life span is approximately 30 years.

Question 86

5 commonest syndromes w low-set ears + 8 others

Answer 86

down, turner, noonan, digeorge, fragile X, cri du chat, goldenhar (unilat), potter, edward, patau, Rubinstein-Taybi syndrome, Smith-Lemli-Opitz syndrome, Treacher Collins syndrome.

Question 87

11 syndromes w cleft lip and palate

Answer 87

pierre-robin, ts13, ts18, fetal phenytoin syndrome, digeorge syndrome, goldenhar syndrome, treacher-collins, stickler, cornelia de lange, smoking, alcohol

Question 88

15 conditions w micrognathia, common when, 2 complications

Answer 88

pierre robin, treacher-collins, russell-silver, potter syndrome, ts 13/18/21, stickler, smith-lemli-opitz, noonan, marfan/EDS, FAS, goldenhar, cri du chat, and many others common in infants but self-corrects usually can make intubation and feeding difficult

Question 89

4 causes of hypertrichosis in young child

Answer 89

mucopolysacc, cornelia de lange syndrome, leprechaunism, treatment w ciclosporin/phenytoin

Question 90

progeria

Answer 90

single gene mutation is responsible for causing progeria: lamin A (LMNA), makes a protein necessary for holding the nucleus of the cell together. When this gene gets mutated, an abnormal form of lamin A protein called progerin is produced development of symptoms is comparable to aging at a rate eight to ten times faster than normal; 1 in 20 million births Children with progeria usually develop the first symptoms during their first few months of life. The earliest symptoms may include a failure to thrive and a localized scleroderma-like skin condition. As a child ages past infancy, additional conditions become apparent, usually around 18–24 months. Limited growth, full-body alopecia (hair loss), and a distinctive appearance (a small face with a shallow, recessed jaw and a pinched nose) are all characteristics Later, the condition causes wrinkled skin, kidney failure, loss of eyesight, and atherosclerosis and other cardiovascular problems; Scleroderma, a hardening and tightening of the skin on trunk and extremities of the body, is prevalent. People diagnosed with this disorder usually have small, fragile bodies, like those of older adults. The head is usually large relative to the body, with a narrow, wrinkled face and a beak nose. Prominent scalp veins are noticeable (made more obvious by alopecia), as well as prominent eyes. Musculoskeletal degeneration causes loss of body fat and muscle, stiff joints, hip dislocations, and other symptoms generally absent in the non-elderly population As there is no known cure, life expectancy of people with progeria is 13 years - at least 90% dying of complications of atherosclerosis

Question 91

cockayne syndrome

Answer 91

rare and fatal (within 12t-2nd decade usually) autosomal recessive neurodegenerative disorder characterized by growth failure, impaired development of the nervous system, abnormal sensitivity to sunlight (photosensitivity), eye disorders and premature aging underlying disorder is a defect in a DNA repair mechanism (proteins CSA and CSB), but unlike other defects of DNA repair, patients with CS are not predisposed to cancer or infection CSA and CSB deficient cells are unable to preferentially repair cyclobutane pyrimidine dimers induced by the action of ultraviolet (UV) light on the template strand of actively transcribed genes, reflecting inability to perform nucleotide excision repair microcephaly, dwarfism, with sunken eyes and an aged look; may see telangiectasia and sensitivity to sunlight (will burn); joint contractures and kyphosis; may have cataracts; sensorineural hearing loss; will see demyelination and intracranial calcification with associated developmental delay, retardation, ataxia, seizures, sensorineural hearing loss etc; severe reflux, may need PEG/RIG

Question 92

cowden syndrome

Answer 92

an autosomal dominant fashion and is part of a spectrum of other disorders that have mutations in the phosphatase and tensin homolog gene (PTEN) - most common in this group; PTEN normally downregs mTOR pathway resulting in decreased cellular proliferation and survival characterized by multiple hamartomas that can occur in any organ. Characteristically, patients with Cowden syndrome develop mucocutaneous lesions and macrocephaly and majority of patients affected with the disease go on to develop a malignant neoplasm of the thyroid, endometrium, or breast Oral lesions are generally papillomatous or a cobblestone pattern and generally are the color of the surrounding mucosa. The tongue and lips are most commonly involved in mucosal lesions, but any part of the mouth can be involved Skin colored to yellow-brown, warty papules on the central face are characteristic features of tricholemmomas; Well circumscribed dermal papules or nodules are a more specific finding in Cowden disease and represent sclerotic fibromas skeletal system may form a high-arched palate, scoliosis, or macrocephaly. More than 85% of patients may have gastrointestinal involvement with hamartomatous polyps. Patients need to have two major criteria to be diagnosed with Cowden disease. (*One of the two must be either Lhermitte-Duclos disease or macrocephaly.) Lhermitte-Duclos disease* Thyroid carcinoma Macrocephaly* Breast cancer Minor Criteria Patients with one major and three of the following minor criteria or four minor criteria may be diagnosed with Cowden disease. Genitourinary tumors or malformations Lipomas Fibromas Mental retardation Fibrocystic disease of the breast Gastrointestinal hamartomas, Other thyroid lesions such as goiter Mucocutaneous lesions or palmoplantar keratosis can meet the criteria alone if 6 or more are present.

Question 93

Simpson-Golabi-Behmel syndrome

Answer 93

an XLR overgrowth syndrome macrosomia and fast growth typically have distinctive facial features, including a large distance between the eyes (hypertelorism), an unusually wide mouth (macrostomia) with a large tongue (macroglossia), and abnormalities of the roof of the mouth (cleft palate +/- cleft lip). Other, findings include extra nipples, various birth defects such as a protrusion of the lining of the abdomen through the area around the belly button (umbilical hernia), and skeletal anomalies. Some people with the condition have a mild to severe intellectual disability. About 10 percent of people with SGBS develop tumors in early childhood, including a rare type of kidney cancer (Wilms tumor) and cancer of the nerve tissue (neuroblastoma)

Question 94

proteus syndrome

Answer 94

rare, congenital hamartomatous syndrome that causes asymmetric and disproportionate overgrowth of limbs, connective tissue nevi, epidermal nevi, dysregulated adipose tissue, and vascular malformations (port wine stains most commonly, may see AVM) less than 100 reported cases, it is 1 in a million to 1 in ten million In most cases, it first appears at 6-18 months of age in an irregular, progressive manner, showing an increase in the discrepancy between the limbs over time

Question 95

weaver syndrome

Answer 95

extremely rare autosomal dominant genetic disorder associated with rapid growth beginning in the prenatal period and continuing through the toddler and youth years another overgrowth syndrome like sotos syndrome or proteus syndrome Weaver syndrome and Sotos syndrome are often mistaken for one another due to their significant phenotypic overlap and similarities Clinical features shared by both syndromes include overgrowth in early development, advanced bone age, developmental delay, and prominent macrocephaly. Mutations in the NSD1 gene may also be another cause for confusion Features distinguishing Weaver syndrome from Sotos syndrome include broad forehead and face, ocular hypertelorism, prominent wide philtrum, micrognathia, deep-set nails, retrognathia with a prominent chin crease, increased prenatal growth, and a carpal bone age that is greatly advanced compared to metacarpal and phalangeal bone age

Question 96

apert syndrome

Answer 96

classified as a branchial arch syndrome, affecting the first branchial (or pharyngeal) arch, the precursor of the maxilla and mandible Craniosynostosis occurs, with bracycephaly the most common pattern giving a high, prominent forehead with a flat back of the skull; risk of raised ICP and mental retardation flat or concave face may develop as a result of deficient growth in the mid-facial bones, leading to a condition known as pseudomandibular prognathism. Other features of acrocephalosyndactyly may include shallow bony orbits and broadly spaced eyes. Low-set ears are also a typical characteristic of branchial arch syndromes will generally have narrow palate with crowding of teeth hands always show: a short thumb with radial deviation complex syndactyly of the index, long and ring finger symbrachyphalangism simple syndactyly of the fourth webspace

Question 97

laurence-moon-biedl syndrome

Answer 97

AR condition with 6 main features: obesity, atypical retinitis pigmentosa, mental deficiency, genital dystrophy/hypogonadism, polydactylism and familial occurrence may have central diabetes insipidus, paraplegia

Question 98

pendred syndrome

Answer 98

AR condition linked to PDS gene on cr 7 (encodes an iodide/chloride transporter found in inner ear and thyroid gland), leading to congenital bilateral (both sides) sensorineural hearing loss and goitre with euthyroid or mild hypothyroidism give levo, support hearing hearing loss of Pendred syndrome is often, although not always, present from birth, and language acquisition may be a significant problem MRI scanning of the inner ear usually shows widened or large vestibular aqueducts with enlarged endolymphatic sacs and this can lead to a conductive as well as sensorineuralm hearing loss

Question 99

mccune albright syndrome

Answer 99

increase in intracellular cAMP signaling is responsible for the clinical manifestations of McCune-Albright syndrome In bone, increased cAMP causes osteoblasts to differentiate into stromal cells while inhibiting further differentiation, resulting in fibrous dysplasia. These fibrous dysplastic lesions then exhibit increased secretion of phosphaturic hormone fibroblastic growth factor-23 (FGF23), causing renal phosphate wasting Increased cAMP signaling in the skin results in stimulation of melanin production via alpha-MSH, resulting in café-au-lait macules. Increased cAMP in endocrine tissue results in increased production and secretion of a specific hormone product. Affected endocrine tissues can include the gonads, thyroid, pituitary, parathyroid, and adrenal glands. Initial clinical presentation is typically due to either precocious puberty or symptoms related to fibrous dysplasia. Females can present with vaginal bleeding and development of breast tissue. Males can present with testicular enlargement, appearance pubic and axillary hair, and increased body odor. Café-au-lait spots may be appreciated in retrospect unless they are prominent. Fibrous dysplastic lesions can present as a pathologic fracture or pain. Lesions of the calvarium and facial bones are common and can present as painless facial asymmetry. Radiographs reveal a characteristic lesion of thinning cortex and intramedullary “ground glass.” Hyperthyroidism is common. Growth hormone and prolactin secretion present as acromegaly and disruption of normal gonadal function. May see macro-orchidism in boys mainstay treatment of gonadotropin-independent precocious puberty is aromatase inhibitors and more recently tamoxifen in females. In the case of the development of central precocious puberty, steady-state gonadotropin-releasing hormone analogs are used to downregulate hypothalamic-pituitary-gonadal axis. Treatment of hyperthyroidism is initially managed medically with antithyroid medications and radioablation. Growth hormone excess treatment is by somatostatin or direct GH receptor antagonists. Hyperprolactinemia management is with bromocriptine. In patients with demonstrated pituitary adenomas, surgical resection of the adenoma is an option. Treatment of hypophosphatemia with oral supplementation is under debate, but supplementation should be used in the setting of rickets. Surgical stabilisation of fibrous dysplasia if progression of pain, stress fracture, deformity, or loss of function

Question 100

schwachmann-diamond syndrome

Answer 100

characterized by: exocrine pancreatic dysfunction with malabsorption, malnutrition, and growth failure; hematologic abnormalities with single- or multilineage cytopenias and susceptibility to myelodysplasia syndrome (MDS) and acute myelogeneous leukemia (AML); and bone abnormalities - short stature, thoracic dystrophy, and others. In almost all affected children, persistent or intermittent neutropenia is a common presenting finding, often before the diagnosis of SDS is made. Short stature and recurrent infections are common. it is the second most common cause of exocrine pancreatic insufficiency in children after CF diagnosis of SDS is established in a proband with the classic clinical findings of exocrine pancreatic dysfunction and bone marrow dysfunction and/or specific genetic mutations Care by a multidisciplinary team is recommended. Exocrine pancreatic insufficiency is treated with oral pancreatic enzymes and fat-soluble vitamin supplementation. Blood and/or platelet transfusions may be considered for anemia and/or thrombocytopenia associated with bi- or trilineage cytopenia. If recurrent infections are severe and absolute neutrophil counts are persistently ≤500/mm3, treatment with granulocyte-colony stimulation factor (G-CSF) can be considered. Hematopoietic stem cell transplantation (HSCT) should be considered for treatment of severe pancytopenia, MDS, or AML.

Question 101

mosaic trisomy 8

Answer 101

Trisomy 8 mosaicism (T8M) is a chromosome disorder caused by the presence of a complete extra chromosome 8 in some cells of the body. The remaining cells have the usual number of 46 chromosomes, with two copies of chromosome 8 in each cell phenotype includes an abnormal facies, reduced joint mobility, various vertebral and costal anomalies, eye anomalies, camptodactyly and deep plantar, and palmar creases. Deep plantar creases are highly characteristics of trisomy 8 mosaicism

Question 102

pallister-killian syndrome

Answer 102

PKS is due to the presence of an extra and abnormal chromosome termed a small supernumerary marker chromosome (sSMC). sSMCs contain copies of genetic material from parts of virtually any other chromosome and, depending on the genetic material they carry, can cause various genetic disorders and neoplasms. The sSMC in PKS consists of multiple copies of the short (i.e. "p") arm of chromosome 12 - thus the contents of 12p are over-expressed in these children syndrome shows genetic mosaicism and so different kids will over-express in different tissues linically PKS is characterized by craniofacial dysmorphism with neonatal frontotemporal alopecia, hypertelorism, and low-set ears as well as kyphoscoliosis, severe intellectual disability, epilepsy, and abnormal muscle tone Numerous other abnormalities may occur including cardiac, dermatologic, gastrointestinal, genitourinary, musculoskeletal, and ophthalmologic anomalies

Question 103

congenital valvulopathies

Answer 103

Endocardial cushion formation is first evident at human embryonic day (E)31–E35 then newly transformed mesenchymal cells within the AV region continue to proliferate resulting in expansion of the endocardial cushions and elongation into valve primordia; expanding endocardial cushions divide the common atrioventricular canal, first by growth of the superior (anterior) and inferior (posterior) endocardial cushions and then by growth of the 2 lateral cushions; the AV canal is divided into the left and right AV valve orifices when the superior and inferior cushions fuse Bicuspid aortic valve (BAV) is the most common valvular malformation, and it affects between 1 % and 2 % of the population; over 35% of these will develop severe complications from BAV, such as aortic valve stenosis and regurgitation, infective endocarditis, ascending aortic aneurysms, and dissection; seen in coarctation of the aorta, turner syndrome, ADPCKD mitral valve prolapse associated with marfan syndrome as well as Ehlers-Danlos (EDS), Stickler, and osteogenesis imperfecta pulmonary stenosis associated with williams syndrome if supravalvular, otherwise noonan syndrome (subvalvular), down syndrome, alagille syndrome, digeorge syndrome, EDS, TOF, rubella exposure in utero

Question 104

kallman syndrome

Answer 104

congenital hypogonadotropic hypogonadism (HH) hypogonadism (HH) that manifests with hypo- or anosmia. This decrease in gonadal function is due to a failure in the differentiation or migration of neurons that arise embryologically in the olfactory mucosa to take up residence in the hypothalamus serving as gonadotropin-releasing hormone (GnRH) neurons. A deficit in the GnRH hormone results in decreased levels of sex steroids leading to a lack of sexual maturity and the absence of secondary sexual characteristics. Typical diagnosis occurs when a child fails to begin puberty. Note other kinds of hypogonad hypogonadism, kallman syndrome is specifically nay of the forms where you also have smelling problems, and it is linked to many different mutations signs can include a lack of testicular development determined by testicular volume in men and a failure to start menstruation (amenorrhea) in women. Poorly defined secondary sexual characteristics can include a lack of pubic hair and underdeveloped mammary glands. Micropenis may also be present in a small portion of male cases, while cryptorchidism or undescended testicles may have been present at birth. These traits are related to low levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH), which consequentially results in low testosterone in males and estrogen and progesterone in women must also have hypo or anosmia cleft palate and lip, hypodontia, and cleft hand or foot are also frequently present along with unilateral renal agenesis; Cerebral impairments may also be present, including central hearing impairment, mirror movements of the hands (synkinesis), and ataxia. Color-blindness and ocular window defects have also been observed hormone testing by paeds endo confirms hypogonad hypogonadism, then genetic screen to try and identify specific causefkline long term HRT for females and testosterone or males or puberty, growth, libido, bone density etc; for males and females, pulsatile GnRH or combined gonadotrophin therapy can be used to induce fertility

Question 105

beckwith wiedeman syndrome

Answer 105

phenotypic presentation of Beckwith-Wiedemann syndrome (BWS) is highly variable, and no consensus clinical diagnostic criteria are universally accepted at this time common features: macroglossia, macrosomia, hemihyperplasia, hyperinsulinaemic hypoglycemia, omphalocele, tumour risk (wilms, hepatoblastoma, neuroblastoma, adrenal tumours), ear pits +/- umbilical hernia Learning difficulties are not part of the condition other than in the very small number of children with a complex chromosome abnormality genetic cause egs: Loss of methylation at IC2 (maternal) in 50%, Gain of methylation at IC1 (maternal), combination of both of those, Heterozygous maternal CDKN1C pathogenic variants, Cytogenetic duplication, inversion, or translocation of 11p15.5, Small chromosomal deletions & duplications, paternal UPD (20% of cases); most of these are sporadic and have low % chance to happen again, some are inherited however - need to knwo specific mutation if suspect 3 genetic things to look for to confirm: constitutional epigenetic or genomic alteration leading to an abnormal methylation pattern at 11p15.5 known to be associated with BWS; OR A copy number variant of chromosome 11p15.5 known to be associated with BWS; OR A heterozygous BWS-causing pathogenic (or likely pathogenic) variant in CDKN1C testing approaches can include DNA methylation studies, single-gene testing, copy number analysis for (sequences within) 11p15.5, chromosomal microarray, karyotype, and use of multigene panels that include genes in the BWS critical region - due to mosaicism if clinically suspicious but initial test negative can repeat, try to use material from an affected area eg from a macroglossia tongue consider other overgrowth syndromes eg perlman, sotos, simpson-golabi-behmal, costello etc other hemihyperplasia syndromes: silver-russel, proteus, NF1 etc hyperinsulinism needs endo input, may need partial pancreatectomy; cleft palate may need surgery; feeding and resp support, maybe tongue reduction surgery needed malignancy surveillance needed: abdominal ultrasound w/views of kidneys needed every 3 mos until age 7 ?wilms tumour; children with KvDMR hypomethylation (the 50% of cases one) do not need this monitoring as they are not at increased risk of wilms tumour Children with hemihypertrophy affecting the legs should be referred for assessment by an orthopaedic surgeon. In many cases, all that is required is a shoe orthotic such as a heel raise. Some children undergo minor surgery later in childhood to slow the growth of the longer leg.

Question 106

clinodactyly what it is and 8 causes

Answer 106

medical term describing the curvature of a digit (a finger or toe) in the plane of the palm, most commonly the fifth finger towards the fourth fairly common isolated anomaly which often goes unnoticed, but also occurs in combination with other abnormalities in certain genetic syndromes: Down syndrome Turner syndrome Cornelia de Lange syndrome 13q deletion syndrome Silver–Russell syndrome Noonan syndrome Ehlers–Danlos syndrome